p-aminobenzenesulphonamides and a process for their manufacture



Patented Aug. 28, 1945 p-AMINOBENZENESULPHONAMIIDES AND A PROCESS FOR THEIR MANUFACTURE Henry Martin, Rudolf Hirt, and'Otto Neracher, Basel, Switzerland, assignors to the Swiss firm of J. R. Geigy A. G., Basel, Switzerland No Drawing. Application March 13, 1942, Serial No. 434,626. In Switzerland April 24, 1941 4 Claims.

It has been found that valuable p-amino-benzenesulphonacylamides of the general formula wherein R means a benzene radical substituted by at least one alkyl and/or alkoxy or alkylthio radical, which benzene radical may also contain further substituents, are obtained, if sulphonamides of the benzene series, which contain a nitrogen containing group in 'p-position to the sulphonamide group, are caused to react with alkyland/or alkoxyor alkylthio-substituted carboxylic acids of the benzene series or functional derivatives thereof and if eventually the p-positioned nitrogen group is converted into an amino group. In the case where two alkyl, alkoxy or alkylthio substituents are present, the same can also be linked together by ring-formation. Compounds of this kind have not hitherto been disclosed; they difier from other p-aminobenzenesulphonacylamides by their improved activity against infection promotersand by a low toxicity.

As sulphonamides of the benzene series containing a nitrogen-containing group in p-position to the sulphonamide group there may be cited: p-aminobenzenesulphonamide, p-acylaminobenzenesulphonamide, p-nitrobenzenesulphonamide and the like. Instead of the nitro group any other group :convertible by reduction into. the amino group may be used, such as for example the nitroso, azo, azoxy or hydrazo group. Azomethine and acylamino groups may be converted into amino groups by hydrolysis. Advantageously such acyl radicals are selected which can again easily be split 01f. As such radicals the following may be for example enumerated: the acetyl or carbomethoxy radical which are again easily split ofif' by a hydrolytic treatment without changing the acylated sulphonamide group.

The sulphonamides of the benzene series substituted in p-position by a nitrogen containing group can be used as such or alsov in form oftheir salts such as for instance p-nitrobenzenesulphonamide of sodium or p-acetylaminobenzenesulphonamide of potassium. The reaction with the acylation agents may also be carried out in the usual manner in the presence of bases such as pyridine, dimethylaniline and the like. As alkyland/or alkoxy-substituted carboxylic acids of the benzene series there may be cited: 0-, -mor ptoluic acid, 2:4-dimethylbenzoic acid, 3:4-dimethylbenzoic acid, 2:5-dimethylbenzoic acid, 4-

chloro- -methylbenzoic acid, 5-chloro-4-methy1 benzoic acid, 4-methoxybenzoic acid, 4-ethoxybenzoic acid, 3:4-dimethoxybenzoic acid, 4-methoxy-5 -methylbenzoic acid,- 5-nitro-4r-methy1benzoic acid, trimethyl ether gallic acid, 3 -acetyl- -amino-4-methylbenzoic acid, piperonylic acid,

benzodioxane carboxylic acid, 4-methylmercaptobenzoic acid, B-methylmercaptobenzoic acid,'4- ethylmercaptobenzoic acid, 4-isopropylmercaptobenzoic acid, 3 methyl-4-methy1mercaptobenzoic acid, 3-methylmercapto-4 methylbenzoic acid and the like. The acids may be used assuch for example in the presence of catalysts, min the form of their functional derivatives, whereby it is also possible to add acid-binding agents'or agents having a condensing effect.

A special embodiment of the present process.

leading to the same products is constituted by the reaction of benzenesulphonhalides containing in p-position a nitrogen containing group, with amides of alkyland/or alkoxyor alkylthio-,

substituted carboxylic acids of the benzene series.

Eventually the p-positioned nitrogen group is to be also converted into an amino group. I

The present invention is, illustrated by the following examples, without being limited thereto.

The parts are by weight, unless otherwise stated.

Example 1 202 parts of p-nitrobenzenesulphonamide are mixed with 170 partsof 4-methoxybenzoic acid chloride in 500 parts by volume of chlorobenzene, then 100 parts of copper powder are added thereto and the whole is boiled, whilestirring, until the development of hydrochloric acid is completed. After about 3 hours the solvent is removed by steam, the residue sucked off, taken up in a sodium carbonate solution having atemperature of C. and, after the addition of some animal charcoal, hot filtered. From the filtrate the final product is precipitated out by means of hydrochloric acid. When crystallised from a1cohe] of strength thisproductmelts at 156 C.

If no copper powder is added to the said mixplace in a considerably Example 2 steam, the residue, which has been sucked off,

is dissolved in 1000 parts of water with the r-' quired quantity of sodium. carbonate and: the solution is filtered clear.

The nitro compound;

is precipitated out from the filtrate hy means of hydrochloric acid. After isolation, the raw:

product possesses the melting point of 1'79 Cl 50 parts of this nitro compound are suspended in 500 parts by volume of water and 2f0 part's by volume of glacial acetic acid with the double quantity of iron filings and reduced ;,a ccording to Bchamp. After completion of the reduction, the whole is-made alkaline'by means of sodium carbonate, "then theii onmud is removed by filtration and the aminocompound precipitated out from the filtrate by m ans '-'of aceticacid. When recrystallised-from alcohol-of 80% strength under-addition of animal-charcoal, this product meltsat187-C-.--

-- Emamplefl 2012 parts of p-nitrobenieiiesiilphonamide are suspended in 75' parts of nitrobenz'ene and brougfitto solution by'addi'fig by portions 13.3 parts of anhydrous aluminium chloride. On allowing 15.4; parts of 4-in'ethylbenzoyl chloride to drop therein, hydrochloric 'acid' is at once developed. The mass is then heated up to 8'0" 100 '01, iiiitil the development of hydrochloric acid has terminated, whereupon'the solution is poured on ice and the nitrobenine removed by s'team-dii'stillatiom' The remaining 4-nitrobei1- zene-N-"M-methylbenz'oyl) -sulphamide is recrystamsea from alcohol or cyeiqnx ncue; Melting ice former colorles neecue offmeltingpoint 45 parts of p nitrobe'n'zenesulphamide are caused to react, as indicated in Example 3, in 200 parts by volume ot nititobenzene inthe pr'es-' ence. of 28 parts of aluminium chloride with 30 parts ofv z niethylbenzoyl chloride. Upon isolation of the :product, there. is obtained the nitro compound which is diifioultly soluble in bicarbonateand shows-amelting point of 186 C.

By. catalytic reduction the corresponding amino compound is obtained which, when recrystallised from alcohol and water, melts at 176 C. I

When instead of the Z-methylbenzoic acid compound in 'the above example; there is used the same quantity-of 3-methy'lbenzoylchloride, there is obtained as intermediate product the m-benzoyl compound of .melting point 126-12'7 C. which is more easily soluble in bicarbonate and which by catalytic reduction is easily converted into the corresponding amino compound.

When crystallised from alcohol, this-compound meltsat 160 C. V

Example 5 I B'Tparts of penitrobenzenesulphamide and 24 partsof aluminium chloride are causedto react in a nitrobenzene solution with 31 parts of 1 2 :4-dimethylbenzoyl chloride. isolation Example 6; 50 parts of p-nitrobenzene-sulphonamide of sodium are suspended in 2'00 parts of nitrobenzene andtreated with 20 parts of 4-methyltmercaptobe'nzcic acid chloride. First stirring is effected for '3"'lioiirs at'room temperature and then the whole iskept for several hours at 90 C. 'I="he miture is stirred with water having condensation {product is precipitated out with diluted hydrochloric acid and directly reduced Icy-means 'of iron. The reduction mixture is made alkaline withsodiumcarbonate, then freed from theiron mud, and from the filtrate the final product 'is precipitated out with acetic acid. When recrystallised from alcohol it shows a melting point of 182 C.

I The -@methylmercaptohenzoicacid is obtained according to Annalender Chemie 436, 217, the acidchloride by reactionwithphosphorus pentachloride; B. P. 05 mm 130C P. 65 C.

- Instead oi. l-methylmercaptobenzoic acid the 3:or.2-methylmercaptobenzoic acid may also be used. The 4-arninobenzenesulphone3'- methylmercaptobenzamide melts at 185. .C., While. '4-aminobenzenesulphone-12methylmercaptobenzamide melts at 177 C.

methyl e imethylniercaptobenzoic acid chloride are added thereto. After I 1 hour the reaction is completed. After dilutiorr' w ith diluted hydrochloric acid the separated product is filtered by suction and recrystallisedfrom alcohol. It constitutes a :yellowislr-zpcwdeccf melting point -..'IYlie.jnitro body is reduced according to Bchamp'by meansof iron and acid, then the reaction mixture is made alkaline aii'd clarified.- From the :filtrate' the reactionproduct is pi-e=' cipitated out by means'otdiluted acetic acid; f11 tered oii 'bysuctionand recrystallised-from alcoh'olunder addition of animal charcoal. -Melting point-.1-92"C.

- The 3emethyl 4emethylmercaptobenzoic'- mic and its chloride may befpreparedas follows:

,22 "parts, of.':3=methyl-=4 aminobenzoic acid (Annalen der Ohemiecl4'4,'168) are h'o-tdi'ss'olved' in'a mixture'of 200 part'siofi'watei' ahd'w parts of concentrated. hydrochloric acid;v ther i the solution is' cooled down to: 540 and diazotised.

While thoroughlyr'stirring', the diazoniu'm so1ution is causedijto-iflow'into' a hot solution of 70? 0. of 26' parts oi-potassium Xanthog'e'nate and 20,,part's-rof sodiumcarbonate in parts oi -water. After, 4 hour cooling isjeifecte'd down to 30 -10. ,the Solution treated. with16.5 parts of solid 'sodium 'hydroxide'and, as soon as the sarhe .is. dissolved, 20' parts of dimethylsulphate are dropped intothissoIutiQn. After 1 hour the whole is boiled fo'r ashort time under reflux,

then distilled with :steam and finally the residue oil, dried and distilled in high-yacuo. Boiling 13011117031 mm.-180 -1 90 0.; meltin g point 166 -167 C 17 parts of 3-methyl-4emethylmercaptobenzoic acid are heated to boiling for 2 hours under reflux with 30 parts by volume of thionyl chloride, the excess thionyl chloride is removed-and distillation carried out. Boiling pointos mm. 135140 C.; melting. point S P-65 C.

Instead of 3-methyl-4-methylmercaptobenzoic acid the isomeric 3 methylmercapto-l-methylbenzoic acid may also be used. The melting point of the 4-aminobenzene-sulphone-3-methylmercapto-4'-methylbenzamide is 217-218 C.

Example 8 28.5 parts of -p-nitrobenzenesulphonamide are dissolved at HP-80 C., while stirring, in 100 parts of absolute pyridine and atthis temperature 30 parts of 4-isopropylmercaptobenzoic acid chloride are slowly addedthereto (preparation of the acid according to Am. Chem. Soc. 62, page 200 (1940),

The nitro compound 'is reducediaccording' to Bchamp as above indicated, the reaction mixture made alkaline and drawn; oii'. From the filtrate the 3:4-dimethylbenzcyl-p-aminobenzenesulphoneamide is precipitated out by means of acetic acid and recrystallised from alcohol. It yields colorless crystals of melting point 222- 223 C.

Instead of the benz enesulphonamide substituted in p-position by a nitro group, which is used in the above examples, there mayquite well be used the other p-substitution products enumerated in the general part. The p-acetyL and carboalkoxy aminobenzene sulphonamides are especiallysuitable. For their use the final productsmay be converted into the metal salts.

By reason of the indications, given in the Examples 1 to 9 p-nitrobenzenesulphonamide or one of its salts respectively may. be acylated with the following carboxylicacid halides; thus there are obtained nitroor amino compounds respectively of the following properties:

Carboxylic acid halide Nitro compound 7 Amino compound, colorless crystals p-E thylbenzoylbromide p-n-Propylbenzoylchloride 3 A-dimethoxybenzoyl chloride 2-methoxyA-methylbenzoylchloride 3-methoxy-4-methylbenzoyl chloride 3-propyl-4-m ethoxybenzoyl chloride 14 3-methyl-4-ethoxybenzoyl chloride M. P. ll4-115 C. (raw) M. P. 152 C. from diluted alcohol under addition of animal charcoal. 15 3-inlethyl-4-isopropylhydroxybenzoylchlor- M. P. 142 C. from diluted alcohol.

16 Piperonylic acid chloride M. P. 197l98 C. from diluted alcohol. 17 Benzodioxanecarboxylic acid chloride M. P. 213214 C. from alcohol under addi- M.P.160162C M. P. l53155 O M. P. 180l85 o. (raw) M. P. 133134 C. from crystallised alcohol.

M. P. 162163 O. crystallised from alcohol.

M. P. 162 C. crystallised from alcohol of 80% strength.

M. P. 200 C. crystallised from alcohol.

M. P. 157 C. crystallised from-dlluted alcohol p-Tert. butylbenzoyl chloride M. Pi1 2ll2 O. crystallised from diluted M11 1.1 232 C. crystallised from diluted alco o a co 0 3-methyl-4-ethylbenzoyl chloride M. P. 17017l C. crystallised from di- M. P. 196' C. crystallised from diluted luted alcohol. I alcohol. Indanecarboxylic acid chloride M. P. 180-1S1 O. crystallised from di- M; P. 2102l1 O. crystallised from alcohol luted alcohol. under addition of charcoal. Tetraline carboxylic acid chloride M. P. 183185 O. crystallised from di- M. P. 220 C. crystallised from diluted luted alcohol. alcohol.

alcohol. M. P. 2l3 O. recrystallised from alcohol.

tion of charcoal.

acid B. P.0.7 mm. 180 C.; M. P. 147-149 0.; by means of thionyl chloride there is obtained the 4-isopropylmercaptobenzoic acid chloride, B. P.1.1 mm. 135--140 C.) The mixture is kept for half an hour at 95 C. and then worked up, as indicated in Example 7. Melting point of the nitro body 175 C.

The nitro body is reduced according to Bchamp; when recrystallised from alcohol, the 4-aminobenzenesulphone-4' isopropylmercaptobenzamide melts at 215 C.

According to the same process the 4-aminobenzenesulphone 3 isopropylmercap'tobenzamide, M. P. 144 C., or the -aminobenzenesulphone-2'-isopropylmercaptobenzamide, M. P. 144 C., can be obtained.

Example 9 In the following the preparation of all of the new compounds used in the above table is described. I

The p-n-butylbenzoyl chloride (see No. 4) is obtained from p-n-butylacetophenone (made from n-butylbenzene, a cetyl chloride and AlCls in CS2) by oxidation with chlorine lye at 60-90 C. The acid (M. P. -98 C.; B. P.0.4 mm. 150-1 55 C.) yields with thionyl-chloride the acid chloride, B. P.1a mm. 145-l50 C.

The 3-methyl-4-ethylbenzoyl chloride (see No. 6) is prepared as follows: m-toluidine is heated up to 280 C. in the autoclave with absolute alcohol and zinc chloride (Journal of the Chemical Society, London, 1934, page 421), whereby 3- methyll-ethylaniline is obtained. From this product the corresponding nitril (B. P.15 mm. C.) is obtained according to Sandmeyer, and from the nitril one obtains the 3-methyl-4-ethylbenzoic acid, M. P. -136 C., by saponification with sulphuric acid of 50% strength during 12 hours. From the latter acid there is obtained the chloride, M. P.13 mm. 135 C., by heating with thionyl chloride on the water bath.

The indane carboxylic acid chloride (see No. 7) is obtained from the carboxylic acid by means The tetraline carboxylic acid chloride (se No; 8) is prepared from acetyltetraline (Journal of Chemical Society, London 1938, page 1290) by oxidation with chlorine lye; from the carboxylic acid which has a melting point of 145 C. there is obtained the acid chloride, B. P.12 mm. 160 C.-, by means of thionyl chloride.

saAcetyltetraline (made from tetraline, acetylchloride and AlCla according to Journal of the Chemical Society, London, 1988, page 1290) is oxidised with chlorine lye on the water-bath. M. P. 143-145 C. From the acid one obtains the acid chloride, B, P.12 mm. 160 C. (see No. 8), when heating on the water-bath with-thionyl chloride in excess.

i The 3-propyl-4-methoxybenzoic'acid (see N0. 12) may for instance easily be obtained from 3- allyl-4-methoxybenzoic acid (No. 1 3) by catalytic reduction. I

The 3-allyl-4-methoxybenzoic acid cl'iloride (see N0. 13) is obtained from 3-al1yl-4-hydroxybenzoic acid ester by methylation with dimethyl sulphate, saponification and interaction with.

isopropylbromide in an alcoholic solution in the autoclave for 10 hours at 140..-150 0., saponifyingthis compound in order to obtainthe free acid (M. P. 145 C.) and causing the latter to react with thionylchloride in excess. pointas mm. 132 C.

Melting The ben zodioxane carboxylic acid chloride (see No. 17) is obtained from acetylbenzodioxane (benzodioxane acetyl chloride in CS2) B. P.o.5

mm. 155 C., M. P. 88 0., by oxidation to the carboxylic acid by .means of chlorine lye, M. P.

of thionyl chloride. Boilingpointiz mm'.140 -]-45 What we claim' isi 1. The p-aminobenzenesulphonamides of the formula wherein .R' represents a benzene radical containing in. p-position to the -NH.CO group a member selected from the group consisting of CH3, OCH3 and SCH3, and in m-position-to the said group a member selected from the group consisting'of H, CH3, OCH3 and SCHa.

2. The p-aminobenzenesulphonamide of the following formula being colorless crystals of the melting point '222' C., when crystallized from alcohol possessing a very high chemotherapeutic activity.

'3. The -p-aminobenzenesulphonamide of the following formula being colorless crystals of the m'elting point 187 C. possessing a very high chemotherapeutic activity when crystallised from alcohol. 4. The p-aminobenzenesulphonamide of the following, formula nmQ-mmmcoQ-scm i CH:

being colorless crystals of the melting point 192' C. possessinga very high chemotherapeutic activity when crystallised from alcohol.

HENRY RUDOLPH HIRT.

OTTO NERACHER. 

